Regularity analysis of nocturnal oximetry recordings to assist in the diagnosis of sleep apnoea syndrome

The relationship between sleep apnoea–hypopnoea syndrome (SAHS) severity and the regularity of nocturnal oxygen saturation (SaO2) recordings was analysed. Three different methods were proposed to quantify regularity: approximate entropy (AEn), sample entropy (SEn) and kernel entropy (KEn). A total of 240 subjects suspected of suffering from SAHS took part in the study. They were randomly divided into a training set (96 subjects) and a test set (144 subjects) for the adjustment and assessment of the proposed methods, respectively. According to the measurements provided by AEn, SEn and KEn, higher irregularity of oximetry signals is associated with SAHS-positive patients. Receiver operating characteristic (ROC) and Pearson correlation analyses showed that KEn was the most reliable predictor of SAHS. It provided an area under the ROC curve of 0.91 in two-class classification of subjects as SAHS-negative or SAHS-positive. Moreover, KEn measurements from oximetry data exhibited a linear dependence on the apnoea–hypopnoea index, as shown by a correlation coefficient of 0.87. Therefore, these measurements could be used for the development of simplified diagnostic techniques in order to reduce the demand for polysomnographies. Furthermore, KEn represents a convincing alternative to AEn and SEn for the diagnostic analysis of noisy biomedical signals.

Obstructive sleep apnoea is associated with sight threatening retinopathy and predicts the developement of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

troduct I on . An observational longitudinal study. P ur P ose . Assess the relationship between obstructive sleep apnoea (OSA) and DR cross-sectionally and longitudinally. M ethods . Adults with Type 2 diabetes mellitus (T2DM), who were re - cruited from a hospital-based diabetes clinic in the UK. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopa - thy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory study (Alice PDX, Philips Respironics, USA). DR was assessed us - ing retinal images between 2007 and 2012. Sight threatening diabetic retinopathy (STDR) was defined as presence of pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. r esults . 199 patients were included (57.3% (n=114) men, 47.7% (n=95) White Europeans). STDR and OSA prevalence were 38.7% (n=77) and 62.8% respectively. A t b A sel I ne . STR prevalence was higher in patients with OSA (OSA+) compared to those without OSA (OSA-) [48.8% n=61 vs. 21.6% n=16, p<0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95% CI 1.6-8.9, p=0.006), maculopathy (OR 4.5, 95% CI 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 95% CI 1.02-15.3, p=0.047). Mild and moderate to severe OSA were independently associated with STR and maculopathy and only moderate to severe OSA was associated with advanced DR following adjustment for con - founders. l ong I tud I n A lly . Over the follow-up period of (4.4±1 years), more OSA+ patients progressed from no or background DR to advanced DR (15.3% (n=17) vs. 3% (n=2), p=0.01). OSA was an independent pre - dictor of advanced DR development after adjustment for confounders (OR 6.6, 95% CI 1.2-35.1, p=0.03). OSA did not predict the develop - ment of maculopathy. c onclus I ons . OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Intervention - al studies are needed to assess the impact of OSA treatment on DR.

Obstructive sleep apnoea predicts the development of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

Background and aims: Diabetic Retinopathy (DR) is a leading cause of blindness. OSA is associated with increased oxidative and nitrosative stress and endothelial dysfunction in patients with type 2 diabetes (T2DM). Hence, it is plausible that OSA can promote the development and progression of DR. Materials and methods: An observational longitudinal study in adults with T2DM. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopathy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory monitoring (Alice PDX, etc.). DR was assesses using retinal images between 2007 and 2012. Sight threatening retinopathy (STR) was defined as pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. Results: 199 patients were included (57.3% men, 47.7% White Europeans). STR and OSA prevalence were 38.7 % and 62.8% respectively. STR preva-lence was higher in patients with OSA (OSA+) compared to those with-out (OSA-) [48.8% vs. 21.6%, p <0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95%CI 1.6-8.9, p=0.006, maculopathy (OR 4.5, 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 1.02-15.3, p=0.047). Over 4.4±1 years, more OSA+ patients progressed from no or background DR to advanced DR (15.3% vs. 3%, p=0.01). OSA was an independent predictor of advanced DR development after adjustment (OR 6.6, 95%CI 1.2-35.1, p=0.03). OSA did not predict the development of maculopathy. Patients received continuous positive airway pressure treatment were less likely to develop advanced DR. Conclusion: OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on DR.Supported by: NIHR (UK) and The UK Novo Nordisk Research Foundation.

Use of CPAP to Reduce Arterial Stiffness in Moderate-to-Severe Obstructive Sleep Apnoea, Without Excessive Daytime Sleepiness (STIFFSLEEP): an Observational Cohort Study Protocol

INTRODUCTION: Sleepiness is a cardinal symptom in obstructive sleep apnoea (OSA) but most patients have unspecific symptoms. Arterial stiffness, evaluated by pulse wave velocity (PWV), is related to atherosclerosis and cardiovascular (CV) risk. Arterial stiffness was reported to be higher in patients with OSA, improving after treatment with continuous positive airway pressure (CPAP). This study aims to assess whether the same effect occurs in patients with OSA and without sleepiness. METHODS AND ANALYSIS: This observational study assesses the CV effect of CPAP therapy on a cohort of patients with moderate-to-severe OSA; the effect on the subcohorts of sleepy and non-sleepy patients will be compared. A systematic and consecutive sample of patients advised CPAP therapy will be recruited from a single outpatient sleep clinic (Centro Hospitalar de Lisboa Central-CHLC, Portugal). Eligible patients are male, younger than 65 years, with confirmed moderate-to-severe OSA and apnoea-hypopnea index (AHI) above 15/hour. Other sleep disorders, diabetes or any CV disease other than hypertension are exclusion criteria. Clinical evaluation at baseline includes Epworth Sleepiness Scale (ESS), and sleepiness is defined as ESS above 10. OSA will be confirmed by polygraphic study (cardiorespiratory, level 3). Participants are advised to undertake an assessment of carotid-femoral PWV (cf-PWV) and 24 hours evaluation of ambulatory blood pressure monitoring (ABPM), at baseline and after 4 months of CPAP therapy. Compliance and effectiveness of CPAP will be assessed. The main outcome is the variation of cf-PWV over time.

The Heavy Vehicle Study : a case-control study investigating risk factors for crash in long distance heavy vehicle drivers in Australia

Background Heavy vehicle transportation continues to grow internationally; yet crash rates are high, and the risk of injury and death extends to all road users. The work environment for the heavy vehicle driver poses many challenges; conditions such as scheduling and payment are proposed risk factors for crash, yet the precise measure of these needs quantifying. Other risk factors such as sleep disorders including obstructive sleep apnoea have been shown to increase crash risk in motor vehicle drivers however the risk of heavy vehicle crash from this and related health conditions needs detailed investigation. Methods and Design The proposed case control study will recruit 1034 long distance heavy vehicle drivers: 517 who have crashed and 517 who have not. All participants will be interviewed at length, regarding their driving and crash history, typical workloads, scheduling and payment, trip history over several days, sleep patterns, health, and substance use. All participants will have administered a nasal flow monitor for the detection of obstructive sleep apnoea. Discussion Significant attention has been paid to the enforcement of legislation aiming to deter problems such as excess loading, speeding and substance use; however, there is inconclusive evidence as to the direction and strength of associations of many other postulated risk factors for heavy vehicle crashes. The influence of factors such as remuneration and scheduling on crash risk is unclear; so too the association between sleep apnoea and the risk of heavy vehicle driver crash. Contributory factors such as sleep quality and quantity, body mass and health status will be investigated. Quantifying the measure of effect of these factors on the heavy vehicle driver will inform policy development that aims toward safer driving practices and reduction in heavy vehicle crash; protecting the lives of many on the road network.

Motivational Interviewing (MINT) improves Continuous Positive Airway Pressure (CPAP) acceptance and adherence : a randomised controlled trial

Objective: Adherence to Continuous Positive Airway Pressure Therapy (CPAP) for Obstructive Sleep Apnoea (OSA) is poor. We assessed the effectiveness of a motivational interviewing intervention (MINT) in addition to best practice standard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA. Method: 106 Australian adults (69% male) with a new diagnosis of obstructive sleep apnoea and clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders centre. Participants were randomly assigned to receive either three sessions of a motivational interviewing intervention ‘MINT’ (n=53; mean age=55.4 years), or no intervention ‘Control’ (n=53; mean age=57.74). The primary outcome was the difference between the groups in objective CPAP adherence at 1 month, 2 months, 3 months and 12 months follow-up. Results: Fifty (94%) participants in the MINT group and 50 (94%) of participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis. The hours of CPAP use per night in the MINT group at 3 months was 4.63 hours and 3.16 hours in the control group (p=0.005). This represents almost 50% better adherence in the MINT group relative to the control group. Patients in the MINT group were substantially more likely to accept CPAP treatment. Conclusions: MINT is a brief, manualized, effective intervention which improves CPAP acceptance and objective adherence rates as compared to standard care alone.

Moderate sleep restriction in treated older male OSA participants: Greater impairment during monotonous driving compared with controls

Objectives To examine the effects on monotonous driving of normal sleep versus one night of sleep restriction in continuous positive airway pressure (CPAP) treated obstructive sleep apnoea (OSA) patients compared with age matched healthy controls. Methods Nineteen CPAP treated compliant male OSA patients (OSA-treated patients (OPs)), aged 50–75 years, and 20 healthy age-matched controls underwent both a normal night’s sleep and sleep restriction to 5 h (OPs remained on CPAP) in a counterbalanced design. All participants completed a 2 h afternoon monotonous drive in a realistic car simulator. Driving was monitored for sleepiness-related minor and major lane deviations, with ‘safe’ driving time being total time driven prior to first major lane deviation. EEGs were recorded continuously, and subjective sleepiness ratings were taken at regular intervals throughout the drive. Results After a normal night’s sleep, OPs and controls did not differ in terms of driving performance or in their ability to assess the levels of their own sleepiness, with both groups driving ‘safely’ for approximately 90 min. However, after sleep restriction, OPs had a significantly shorter (65 min) safe driving time and had to apply more compensatory effort to maintain their alertness compared with controls. They also underestimated the enhanced sleepiness. Nevertheless, apart from this caveat, there were generally close associations between subjective sleepiness, likelihood of a major lane deviation and EEG changes indicative of sleepiness. Conclusions With a normal night’s sleep, effectively treated older men with OSA drive as safely as healthy men of the same age. However, after restricted sleep, driving impairment is worse than that of controls. This suggests that, although successful CPAP treatment can alleviate potential detrimental effects of OSA on monotonous driving following normal sleep, these patients remain more vulnerable to sleep restriction.

One night’s CPAP withdrawal in otherwise compliant OSA patients: marked driving impairment but good awareness of increased sleepiness

Purpose Obstructive sleep apnoea (OSA) patients effectively treated by and compliant with continuous positive air pressure (CPAP) occasionally miss a night’s treatment. The purpose of this study was to use a real car interactive driving simulator to assess the effects of such an occurrence on the next day’s driving, including the extent to which these drivers are aware of increased sleepiness. Methods Eleven long-term compliant CPAP-treated 50–75-year-old male OSA participants completed a 2-h afternoon, simulated, realistic monotonous drive in an instrumented car, twice, following one night: (1) normal sleep with CPAP and (2) nil CPAP. Drifting out of road lane (‘incidents’), subjective sleepiness every 200 s and continuous electroencephalogram (EEG) activities indicative of sleepiness and compensatory effort were monitored. Results Withdrawal of CPAP markedly increased sleep disturbance and led to significantly more incidents, a shorter ‘safe’ driving duration, increased alpha and theta EEG power and greater subjective sleepiness. However, increased EEG beta activity indicated that more compensatory effort was being applied. Importantly, under both conditions, there was a highly significant correlation between subjective and EEG measures of sleepiness, to the extent that participants were well aware of the effects of nil CPAP. Conclusions Patients should be aware that compliance with treatment every night is crucial for safe driving.

One night CPAP withdrawal impairs performance at a driving simulator task faster than sleep restriction to 5 hours with treatment in OSA patients

Introduction Sleep restriction and missing 1 night’s continuous positive air pressure (CPAP) treatment are scenarios faced by obstructive sleep apnoea (OSA) patients, who must then assess their own fitness to drive. This study aims to assess the impact of this on driving performance. Method 11 CPAP treated participants (50–75 yrs), drove an interactive car simulator under monotonous motorway conditions for 2 hours on 3 afternoons, following;(i)normal night’s sleep (average 8.2 h) with CPAP (ii) sleep restriction (5 h), with CPAP (iii)normal length of sleep, without CPAP. Driving incidents were noted if the car came out of the designated driving lane. EEG was recorded continually and KSS reported every 200 seconds. Results Driving incidents: Incidents were more prevalent following CPAP withdrawal during hour 1, demonstrating a significant condition time interaction [F(6,60) = 3.40, p = 0.006]. KSS: At the start of driving participants felt sleepiest following CPAP withdrawal, by the end of the task KSS levels were similar following CPAP withdrawal and sleep restriction, demonstrating a significant condition, time interaction [F(3.94,39.41) = 3.39, p = 0.018]. EEG: There was a non significant trend for combined alpha and theta activity to be highest throughout the drive following CPAP withdrawal. Discussion CPAP withdrawal impairs driving simulator performance sooner than restricting sleep to 5 h with CPAP. Participants had insight into this increased sleepiness reflected by the higher KSS reported following CPAP withdrawal. In the practical terms of driving any one incident could be fatal. The earlier impairment reported here demonstrates the potential danger of missing CPAP treatment and highlights the benefit of CPAP treatment even when sleep time is short.

Countermeasures to driver sleepiness : is the message getting through?

The most effective countermeasures to driver sleepiness (caffeine and a nap, ideally in combination) are not the most popular choice for UK drivers. Groups susceptible to driver sleepiness (OSA patients and truck drivers) do not favour effective countermeasures to driver sleepiness. Prior experience of driver sleepiness does not promote an effective choice of countermeasure.

Sleep-related eye symptoms and their potential for identifying driver sleepiness

The majority of individuals appear to have insight into their own sleepiness, but there is some evidence that this does not hold true for all, for example treated patients with obstructive sleep apnoea. Identification of sleep-related symptoms may help drivers determine their sleepiness, eye symptoms in particular show promise. Sixteen participants completed four motorway drives on two separate occasions. Drives were completed during daytime and night-time in both a driving simulator and on the real road. Ten eye symptoms were rated at the end of each drive, and compared with driving performance and subjective and objective sleep metrics recorded during driving. ‘Eye strain’, ‘difficulty focusing’, ‘heavy eyelids’ and ‘difficulty keeping the eyes open’ were identified as the four key sleep-related eye symptoms. Drives resulting in these eye symptoms were more likely to have high subjective sleepiness and more line crossings than drives where similar eye discomfort was not reported. Furthermore, drivers having unintentional line crossings were likely to have ‘heavy eyelids’ and ‘difficulty keeping the eyes open’. Results suggest that drivers struggling to identify sleepiness could be assisted with the advice ‘stop driving if you feel sleepy and/or have heavy eyelids or difficulty keeping your eyes open’.

Home monitoring for infants at risk of the sudden infant death syndrome

This study evaluates the effectiveness and social implications of home monitoring of 31 infants at risk of sudden infant death syndrome (SIDS). Thirteen siblings of children dying of SIDS, nine near miss SIDS infants and nine preterm infants with apnoea persisting beyond 40 weeks post conceptual age were monitored from a mean age of 15 days to a mean of 10 months. Chest movement detection monitors were used in 27 and thoracic impedance monitors in four. Genuine apnoeic episodes were reported by 21 families, and 13 infants required resuscitation. Apnoeic episodes occurred in all nine preterm infants but in only five (38%) of the siblings of SIDS (P<0.05). Troublesome false alarms were a major problem occurring with 61% of the infants and were more common with the preterm infants than the siblings of SIDS. All but two couples stated that the monitor decreased anxiety and improved their quality of life. Most parents accepted that the social restrictions imposed by the monitor were part of the caring process but four couples were highly resentful of the changes imposed on their lifestyle. The monitors used were far from ideal with malfunction occurring in 17, necessitating replacement in six, repair in six and cessation of monitoring in three. The parents became ingenious in modifying the monitors to their own individual requirements Although none of these 31 ‘at risk’ infants died the study sample was far too small to conclude whether home monitoring prevented any cases of SIDS.

Natural history of idiopathic erythrocytosis - A retrospective case series review

Idiopathic Erythrocytosis (IE) is a diagnosis given to patients who have an absolute erythrocytosis (red cell mass more than 25% above their mean normal predicted value) but who do not have a known form of primary or secondary erythrocytosis (BCSH guideline, 2005). We report here the results of a follow-up study of 80 patients (44 male and 36 female) diagnosed with IE from the United Kingdom and the Republic of Ireland over a 10 year period. Baseline information was initially collected when investigating for molecular causes of erythrocytosis in this group. The diagnosis of IE was made on the basis of a raised red cell mass >25% above mean normal predicted value, absence of Polycythaemia Vera (PV) based on the criteria of Pearson and Messinezy (1996), and the exclusion of secondary erythrocytosis (oxygen saturation >92% on pulse oximetry, no history of sleep apnoea, no renal or hepatic pathology, and a normal oxygen dissociation curve (if indicated). The average age at diagnosis of erythrocytosis was 34.5 (2–74 years). Erythropoietin levels were available for 77/80 of the patients and were low in 18 (23%) and normal or high in 59 (74%). Ultrasound imaging was carried out in 67 patients (84%) at time of diagnosis and no significant abnormalities found. Fourteen patients had a family history of erythrocytosis. These patients have now been followed up for an average of 9.4 years (range 1–39). Out of 80 patients 56 patients can still be classified as having IE, of whom 52 are living (cause of death in the other 4 - lung cancer, RTA, sepsis, unknown). Thirty-five of these patients are regularly venesected, 3 take hydroxyurea (one also venesected), 11 receive no treatment while treatment is unknown in 2. Twenty take aspirin, 1 warfarin and 31 no thromboprophylaxis. Four of these patients had suffered thromboembolic complications (3 with CVA/TIAs and 1 with recurrent DVT) at or before their original diagnosis. Since diagnosis 8 patients have had 9 thrombotic events of which 7 were arterial (1 CVA, 3 TIAs, 1 MI, 2 PVD) and 2 venous (DVT/PE). Twenty take aspirin, 1 dipyridamole, 1 warfarin and 30 take no thromboprophylaxis. Out of the 24 patients who now have a diagnosis other than IE, 8 have been diagnosed with myelo-proliferative disease. Thirteen patients have a molecular abnormality which is likely to account for their erythrocytosis (11 VHL, 1 PHD-2, 1 EPO-receptor mutations). Three patients have secondary erythrocytosis. Older case studies identified a heterogenous group of patients, some of whom probably had apparent erythrocytosis and some who had either primary polycythaemia or secondary causes later identified (Modan and Modan, Najean et al). More recent reviews have identified a more homogenous group with low rates of transformation to myelofibrosis/acute leukaemia and low rates of thrombosis of around 1% patient-year. Follow up of our initial patient group does indeed reveal a heterogeneous group of patients with 10% now diagnosed with an MPD, although when analysis is confined to those patients who continue to fulfil the criteria for IE, the clinical course has been more stable. There has been no progression to MDS or leukaemia in this group (one patient with PV progressed to AML). The rate of thrombosis is 1.6% patient-years which is lower than the rate seen in PV and is consistent with the rate identified in other series. Molecular defects continue to be identified in this group and future investigation is likely to reveal further abnormalities.

Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry

Objective: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.
Design: Cross-sectional observational study.Setting The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry.
Participants: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)—severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).
Main outcome measures: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.
Results: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.

Conclusions: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.

Alteraciones respiratorias durante el sueño en niños con Síndrome Down a la altura de Bogotá

Objetivo: determinar la frecuencia de las diferentes alteraciones respiratorias durante el sueño (ARS) e hipertensión pulmonar (HTP) y establecer la saturación de oxígeno (SpO2) en vigilia, sueño y durante los eventos en niños con Síndrome Down (SD) a la altura de Bogotá (2640m) de acuerdo a grupos de edad e IMC. Métodos: estudio descriptivo de corte transversal, se incluyeron todos los niños con SD con sospecha de ARS remitidos a polisonograma (PSG) de octubre de 2011 a enero de 2013 a la Fundación Neumológica Colombina (FNC). Se dividieron en 3 grupos: apnea obstructiva, apnea obstructiva y central, sin apneas. Resultados: 74 niños, el 36,5% mujeres, edad media 4 años. 47,3% presento apnea obstructiva, más frecuente en >2 años, 35,1% apnea obstructiva y central, más frecuente en < 2 años y 17,6 % sin apnea. SpO2 promedio en apnea obstructiva 84,63%, apnea obstructiva y central: 81,8% y sin apnea: 86,85% (p 0,058). 23% presento obesidad, 16% con apnea obstructiva. 53 pacientes tenían ecocardiograma: 28% HTP, 53,3% tuvo apnea obstructiva y 26,7 apnea obstructiva y central, no diferencias significativas. SpO2 promedio en HTP 88,3% vigilia, 86,2% sueño REM, 85,7 % sueño no REM, no diferencia significativa comparada con pacientes sin HTP. Conclusiones: Las ARS son frecuentes en los niños con SD, La desaturación está presente en los niños con SD independiente del tipo de apnea. A todos los niños SD se les debe practicar un PSG en el primer año de vida.